The present invention relates to a new and useful device and method that utilizes trifluoropropylmethyl/dimethyl siloxane elastomer to locally deliver oxybutynin in a controlled manner for treating urinary incontinence for up to twenty-eight contiguous days, or as needed.
Urinary incontinence is a debilitating disorder which afflicts at least 15% of the elderly population, and is present in approximately 50% of institutionalized elderly persons. Indeed, many elderly people are institutionalized because of their urinary incontinence. The costs for caring for such patients is extremely high, particularly since they require constant monitoring and changing of their clothes and bedding.
The elderly, however, are not the only group of the population that suffers from urinary incontinence. This disorder is also prevalent in postmenopausal women. In particular, pelvic relaxation due to childbirth can cause uterine prolapse and cystocele, which allows descent of the normal urethrovesical angle and contributes to urinary incontinence. The ramifications of the natural aging process in women, such as decreased levels of estrogen, also may result in urinary incontinence.
The therapeutic effect of oxybutynin (4-diethylamino-2-butynylphenylcyclohexylglycolate), which is described in the 1992 Physician""s Desk Reference, pages 1332-1333 (with reference to the drug xe2x80x9cDITROPANxe2x80x9d manufactured by Marion Merrill Dow), is well documented [Yarker, Y. E., Goe, K. L. and Fitton, A., Oxybutynin: A Review of its Pharmacodynamic and Pharmacokinetic Properties, and its Therapeutic Use in Detrusor Stability. Drugs and Aging 6(3):243-265 (1995)]. In particular, oxybutynin has an anticholinergic and spasmolytic effect on the bladder that leads to relaxation of the detrusor muscle, fewer spontaneous contractions, a decrease in the frequency and urge to urinate, and increased bladder-filling capacity.
Traditionally, oxybutynin has been administered orally at relatively high doses (5 mg tablets taken two to four times a day). Oxybutynin has also been incorporated into tablets, capsules, granules and pills containing 1-5 mg, preferably 5 mg of oxybutynin chloride, and syrups containing 1-5 mg, preferably 5 mg of oxybutynin chloride per 5 ml, and transdermal compositions (creams or ointments) containing 1-10 weight percent (wt %) oxybutynin chloride. Such administration techniques inherently permit oxybutynin to circulate throughout the body. Unfortunately however, oxybutynin has deleterious side effects when administered systemically. More specifically, anticholinergic side effects such as dry mouth, dry eyes, blurred vision, constipation, and headaches have been observed when oxybutynin is orally delivered. Moreover, N-desethyloxybutynin, a metabolite of oxybutynin produced in the liver, has similar antimuscarinic activity, and hence can have much of the same effects as oxybutynin both on the bladder""s detrusor muscle and in other organs [Yarker, et al; Westlin, L., Anticholinergic Effects of Two Metabolites of Oxybutynin, Research Report No. 840625F, data on file, Smith and Nephew Pharmaceuticals, Ltd., 1985; Hughes, K. M., Lang, J. C. T., Lazare, R., et al., Measurement of Oxybutynin and its N-desethyl metabolite in Plasma, and its Application to Pharmacokinetic Studies in Young, Elderly and Frail Volunteers. Xenobiotica 22(7):859-69 (1992); Waldeck, K., Larsson, B., Andersson, K. E., Comparison of Oxybutynin and its Active Metabolite, N-desethyloxybutynin, in the Human Detrusor and Parotid Gland. Jnl. Of Urology 157:1093-97 (1997)]. Oral administration in particular has been shown to result in peak blood concentrations of the metabolite that are 6-9 times higher than the concentration of oxybutynin itself. Furthermore, the area under the plasma time concentration curve (or AUC, which measures the gross amount of drug present over time) is also higher for the metabolite (10-12 times) than for oxybutynin.
In order to ameliorate the effects of oxybutynin in the body and to limit the production of metabolite, efforts have been made to administer oxybutynin intravesically. Such delivery has demonstrated that oxybutynin can be delivered directly to the bladder of a patient, limit the circulation of oxybutynin in the body, and the deleterious side effects. However, intravesical delivery possesses inherent limitations. Initially, intravesical administration occurs through a catheter 3-4 times a day, and therefore is a cumbersome modality suited only to relatively immobile patients. Another limitation is that such delivery is uncomfortable to the patient. A major limitation of intravesical administration is that this method is simply not suited to frequent, long term use for most incontinence suffers.
Accordingly, what is needed is a new and useful device which delivers oxybutynin locally, i.e., directly to the detrusor muscle, in a controlled manner, and does not rely solely upon the body""s circulatory system for such delivery. As a result, systemic circulation of oxybutynin and its metabolite to other body sites can be limited.
What is also needed is a new and useful device which is capable of locally delivering and controllably releasing a therapeutically effective amount of oxybutynin to a patient""s detrusor muscle for up to twenty-eight (28) contiguous days. The citation of any reference herein should not be construed as an admission that such reference is available as xe2x80x9cPrior Artxe2x80x9d to the instant application.
There is provided, in accordance with the present invention, a device and method for locally delivering and controllably releasing a therapeutically effective amount of oxybutynin to the detrusor muscle in order to treat urinary incontinence in a female.
Broadly, the present invention extends to a device for locally delivering and controllably releasing oxybutynin to the cervical region of a female to treat urinary incontinence, wherein the device comprises a ring having a surface, and a bore running from the surface into the ring, wherein the ring comprises trifluoropropylmethyl/dimethyl siloxane elastomer. The ring of a device of the invention has a sufficient size such that it can be inserted into the vaginal canal of the female. Furthermore, a device of the invention comprises a pharmaceutical composition located within the bore, wherein the pharmaceutical composition comprises oxybutynin and an excipient. A device of the present invention also comprises a cap on the bore at the surface of the ring, wherein the cap prevents the pharmaceutical composition from diffusing out of the bore at the surface of the ring. Upon insertion of the ring into the vaginal canal, oxybutynin is controllably released from the ring in a therapeutically effective amount to treat the urinary incontinence.
A ring of a device of the invention can further comprise a first portion comprising trifluoropropylmethyl/dimethyl siloxane elastomer having a bore therein, and a second portion comprising a material into which oxybutynin is insoluble, such as a barium sulfate composite. A ring of a device of the invention can also comprise a first portion comprising trifluoropropylmethyl/dimethyl siloxane elastomer having a bore running from the surface of the first portion into the first portion, a second portion comprising polydimethylsiloxane elastomer, or a barium sulfate composite, and at least two shields located between the first and second portions, wherein the at least two shields comprise a material into which oxybutynin is insoluble, e.g., a barium sulfate composite or polytetrafluorethylene (PTFE). The two shields intersect the first and second portions, and prevent contact between the first and second portions. In a particular embodiment, the one bore intersects the surface of the first portion twice, and is capped at both ends with caps described above. As a result, the trifluoropropylmethyl/dimethyl siloxane elastomer of the first portion controllably releases oxybutynin contained within the bore, and the barium sulfate composite shields prevent diffusion of oxybutynin to other parts of the ring. In another embodiment, wherein the first and second portions comprise trifluoropropylmethyl/dimethyl siloxane elastomer, the bore comprises a first bore which runs from the surface of the first portion into the first portion, and a second bore running from the surface of the second portion into the second portion. Optionally the bores can intersect the surface of the ring at two different points. Naturally, the cap of the invention comprises a sufficient number of caps to cover both bores, so that the pharmaceutical composition within the bore(s) is prevented from diffusing uncontrollably from the bore at the surface of the ring.
Alternatively, a ring of a device of the invention comprises four portions and four shields such that each shield intersects two portions, and each portion is prevented from contacting any other portion. At least one of the portions comprises trifluoropropylmethyl/dimethyl siloxane elastomer having a bore running from the surface of the portion into the portion. Other portions of the ring can comprise polydimethylsiloxane, barium sulfate composite, or a combination thereof.
In addition, the present invention extends to a device for locally delivering and controllably releasing oxybutynin as described above, wherein the amount of oxybutynin in the pharmaceutical composition can vary, depending upon the desired dose to be administered to the patient. In a particular embodiment, the pharmaceutical composition comprises about 60% by weight oxybutynin and about 40% by weight an excipient, e.g., tin catalyzed silicone polymer. Naturally, the oxybutynin can be in a free base form, a salt, or a mixture thereof. Optionally, the pharmaceutical composition comprises a rod which is inserted into the one bore(s) of the ring. Methods of producing such rods are described infra. A therapeutically effective amount of oxybutynin that can be locally delivered with a device of the invention ranges from about 0.5 mg/day to about 5.0 mg/day as needed. In a particular embodiment, a device of the present invention can locally deliver a therapeutically effective amount of oxybutynin for up to twenty-eight contiguous days.
Moreover, the present invention extends to a device as described above, wherein caps are placed over the bore at the surface of the ring. Consequently, an oxybutynin pharmaceutical composition can be held within the bore of a ring of a device of the invention, and come into direct contact with the trifluoropropylmethyl/dimethyl siloxane elastomer of the ring, and be contained within the bore. Numerous materials can serve as caps in a ring of a device of the invention. Particular examples of such materials include, but certainly are not limited to trifluoropropylmethyl/dimethyl siloxane elastomer, and polydimethylsiloxane (PDMS), to name only a few.
In another embodiment, the present invention extends to a device for locally delivering and controllably releasing oxybutynin to the cervical region of a female to treat urinary incontinence, wherein the device comprises:
(a) a ring having a surface, and a bore which runs from the surface into the ring, wherein the ring comprises trifluoropropylmethyl/dimethyl siloxane elastomer, and the ring has a sufficient size such that it can be inserted into the vaginal canal of the female;
(b) a pharmaceutical composition located within the bore, wherein the pharmaceutical composition comprises 60% by weight oxybutynin and 40% by weight tin catalyzed silicone polymer;
(c) a cap which covers the bore at the surface of the ring, wherein the cap comprises polydimethylsiloxane,
such that upon insertion of the ring into the vaginal canal, the oxybutynin is controllably released from the ring in a therapeutically effective amount to treat the urinary incontinence. Optionally, the bore intersects the surface of the ring twice, and thus requires two caps, one to cover the bore at each point it intersects the surface of the ring.
The present invention further extends to a method for locally delivering and controllably releasing a therapeutically effective amount of oxybutynin in the cervical region of a female to treat urinary incontinence. An initial step of a method of the invention comprises providing a ring having a surface, and a bore running from the surface into the ring. A pharmaceutical composition comprising oxybutynin and an excipient is located within the bore. Moreover, the ring comprises of trifluoropropylmethyl/dimethyl siloxane elastomer, which controllably releases oxybutynin, and has a sufficient size such that it can be inserted into the vaginal canal of the female. Furthermore, a ring of a method of the invention comprises a cap which covers the bore at the surface of the ring, so that the pharmaceutical composition is contained within the bore. The ring is then inserted into the vaginal canal of the female. Once in the vaginal canal, a therapeutically effective amount of oxybutynin is controllably released from the ring, and treats the female""s urinary incontinence.
In addition, the present invention extends to a method of treating urinary incontinence in a female as described above, wherein the ring comprises a first portion comprising trifluoropropylmethyl/dimethyl siloxane elastomer, a second portion comprising a barium sulfate composite or polydimethylsiloxane, and the bore runs from the surface of the first portion into the first portion of the ring.
The present invention further extends to a method of treating urinary incontinence in a female, wherein the ring comprises at a first portion comprising trifluoropropylmethyl/dimethyl siloxane elastomer, a second portion comprising trifluoropropylmethyl/dimethyl siloxane elastomer, a barium sulfate composite or polydimethylsiloxane, and at least two shields comprising a material into which oxybutynin is insoluble, .e.g., a barium sulfate composite or polytetrafluoroethylene, wherein the at least two shields are located between the first and second portions and prevent contact between the first and second portions. The bore runs from the surface of the first portion into the first portion. Furthermore, a method of the invention extends to a ring comprising a first bore running from the surface of the first portion into the first portion, and intersecting the surface of the first portion twice. Additionally, in a ring in which the second portion comprises trifluoropropylmethyl/dimethyl siloxane elastomer, the ring further comprises a second bore which runs from the surface of the second portion into the second portion. Optionally, the second bore intersects the surface of the second portion twice. Naturally, a sufficient number of caps comprising a material such as trifluoropropylmethyl/dimethyl siloxane elastomer, polydimethylsiloxane, polytetrafluoroethylene, etc. are used in a ring of a method of the invention to cover the bore(s) at intersection points with the surface of the ring so that the pharmaceutical composition is contained within the bore(s).
As explained above, a pharmaceutical composition of a method of the invention comprises oxybutynin and an excipient, such as tin catalyzed silicone polymer. The therapeutically effective amount of oxybutynin locally delivered and controllably released with a method or device of the invention can vary, depending upon the particular needs of the patient. In a particular embodiment, the pharmaceutical composition comprises about 60% by weight oxybutynin and about 40% by weight excipient, such as tin catalyzed silicone polymer. Such a composition can be used to locally deliver and controllably release a therapeutically effective amount of oxybutynin ranging from about 0.5 mg/day to about 5 mg/day, for up to 28 days. Data of delivery of oxybutynin for 28 contiguous days is set forth in FIG. 5.
In another embodiment, the present invention extends to a method for locally delivering and controllably releasing a therapeutically effective amount of oxybutynin in the cervical region of a female to treat urinary incontinence, comprising the steps of:
(a) providing a ring comprising polydimethylsiloxane, trifluoropropylmethyl/dimethyl siloxane elastomer, a barium sulfate composite, or a combination thereof, wherein the ring has a sufficient size such that it can be inserted into the vaginal canal of the female, and comprises a bore in the trifluoropropylmethyl/dimethyl siloxane elastomer which runs from the surface of the ring into the ring,
(b) inserting a pharmaceutical composition comprising oxybutynin and an excipient weight tin catalyzed silicone polymer within the bore;
(c) placing a cap on the bore at the surface of the ring; and
(d) inserting the ring into the vaginal canal of the female.
Once in the vaginal canal, a therapeutically effective amount of oxybutynin ranging from about 0.5 mg/day to about 5 mg/day is controllably released from the ring for up to twenty eight days. A ring having applications herein can comprise a first portion comprising trifluoropropylmethyl/dimethyl siloxane elastomer, and a second portion comprising a barium sulfate composite, polydimethylsiloxane or trifluoropropylmethyl/dimethyl siloxane elastomer, wherein the bore runs from the surface of the first portion into the first portion. Optionally, the bore intersects the surface of the first portion twice. Furthermore, in a ring comprising a second portion which comprises trifluoropropylmethyl/dimethyl siloxane elastomer, the bore further comprises a second bore which runs from the surface of the second portion into the second portion. Pharmaceutical composition is contained within both bores. Optionally, the second bore intersects the surface of the second portion twice. Naturally, a ring of a device of the invention comprises a sufficient number of caps to cover the points of intersection between the surface and the bore(s) so that the pharmaceutical composition is contained within the bore(s).
Moreover, a ring having applications in a method of the invention can comprise a first and a second portion, and at least two shields comprising a pharmaceutically acceptable inert material into which oxybutynin is insoluble, such as a barium sulfate composite or polytetrafluoroethylene. At least two shields are located between the first and second portions, and prevent contact between these two portions. In a particular embodiment, the first portion comprises trifluoropropylmethyl/dimethyl siloxane elastomer, and the second portion comprises trifluoropropylmethyl/dimethyl siloxane elastomer, polydimethylsiloxane, or a barium sulfate composite. The bore comprises a first bore located in the first portion. Optionally, the first bore intersects the surface of the first portion twice. Furthermore, if the second portion comprises trifluoropropylmethyl/dimethyl siloxane elastomer, the bore further comprises a second bore which runs from the surface of the second portion into the second portion. Optionally, the second bore intersects the surface of the second portion twice. Naturally, a sufficient number of caps are used to cover the intersection points of the bore(s) and the surface of the ring in order to contain the pharmaceutical composition within the bore(s).
Furthermore, the present invention extends to a method for locally delivering and controllably releasing a therapeutically effective amount of oxybutynin in the cervical region of a female to treat urinary incontinence, as described above, wherein the ring comprises first and second portions, and at least two shields into which oxybutynin is insoluble. The at least two shields are located between the first and second portions of the ring, and prevent contact between the first and second portions. Examples of substances which form such shields include a barium sulfate composite or polytetrafluoroethylene, to name only a few. Either the first portion, the second portion or both portions of the ring can comprise trifluoropropylmethyl/dimethyl siloxane elastomer. Moreover, when the second portion of the ring also comprises trifluoropropylmethyl/dimethyl siloxane elastomer, the bore further comprises a second bore which runs from the surface of the second portion into the second portion. Optionally, the bore intersects the first portion twice, and the second bore intersects the surface of the second portion twice. Naturally, a sufficient number of caps as described above are used to cover the intersection points of the bore(s) and the surface of the ring in order to contain the pharmaceutical composition within the bore(s).
The present invention further extends to a method for locally delivering and controllably releasing a therapeutically effective amount of oxybutynin in the cervical region of a female to treat urinary incontinence, as described above, wherein the pharmaceutical composition comprises about 60% by weight oxybutynin and about 40% by weight an excipient, preferably tin catalyzed silicone polymer. In a particular embodiment, the pharmaceutical composition is in the shape of a rod, which is inserted into the bore of the ring.
Accordingly, it is a principal object of the present invention to provide a device and method for treating urinary incontinence which locally delivers and controllably releases oxybutynin in the cervical region of a female so that the oxybutynin can diffuse directly to, and interact with the detrusor muscle.
It is another object of the present invention to utilize the heretofore unknown ability of trifluoropropylmethyl/dimethyl siloxane elastomer to controllably release oxybutynin.
It is still another object of the invention to provide a device and method for treating urinary incontinence which locally delivers and controllably releases a therapeutically effective amount of oxybutynin to the female for up to twenty-eight contiguous days.
It is yet another object of the invention to provide a device and method for treating urinary incontinence wherein the therapeutically effective amount of oxybutynin delivered to the patient can be tailored to the patient""s needs.
These and other aspects of the present invention will be better appreciated by reference to the following drawings and Detailed Description.